Professional antigen-presenting-cells (APC) are essential to initiate a primary immune response in a non-immune, naive animal. The most important APC is the Dendritic Cell (DC), which is found as an interdigitating cell at all regions of the body, at an interface with the environment (i.e. skin and mucosal surfaces such as the lung, airways, nasal passage etc). Antigens presented by DCs are profoundly immunogenic. One important phenotypic marker of the DC is a very high level of surface MHC class II expression. Activated DCs migrate to secondary lymph nodes to “prime” both CD4 and CD8 T cells which proceed as antigen activated effector cells, to proliferate, produce cytokines and regulate the humoral response of B-lymphocytes. Thus, antigen presentation by DC appears to be the obligate first step in any adaptive immune response. Other APCs such as macrophages and B-cells appear to be important in later, secondary responses and by themselves are not effective in the initial priming of a response. Thus the DC is generally regarded as the most important cell to target for enhancement of immune responses.
The targeting of antigens to DC can however be problematic. For example, many peptides by themselves are poorly antigenic and immunogenic because they are not efficiently delivered to APC in vivo. They are equally not taken up by APC very efficiently and do not elicit the second signals required for efficient antigen presentation.
Superantigens are a family of semi-conserved bacterial proteins that target the immune system by binding simultaneously to the T cell Receptor (TcR) via the Vβ domain on T lymphocytes and MHC class II molecules expressed on APC including dendritic cells.
Superantigens (SAgs) are the most potent immune mitogens known and activate large numbers of T cells at femto-attomolar concentrations (10−15-10−18M). They cause significant toxicity due to the massive systemic cytokine release by T cells. There are currently 19 members of the staphylococcal and streptococcal superantigen family.
Terman (WO 98/26747)1 discloses therapeutic compositions employing superantigens. It is suggested that superantigens, in conjunction with one or more additional immunotherapeutic antigens, may be used to either induce a therapeutic immune response directed against a target or to inhibit a disease-causing immune response. Terman further describes the formation of immunotherapeutic antigen-superantigen polymers. Such polymers include those where the superantigen component is coupled to a peptide antigen by a secondary amine linkage. However, there is no teaching or suggestion by Terman that the superantigen component be one from which the TcR binding function has been wholly or partly ablated. Indeed, there is no recognition that a TcR binding is not essential to activation of APCs and to stimulation of an immune response against the antigenic component of the polymer.
Thus, wild-type SAgs, or modified SAgs which retain the ability to bind to TcR, are of little use because they themselves elicit massive, indiscriminate T cell responses by binding to the TcR. This TcR cross-linking appears to be the major cause of their toxicity2.
There exists a need therefore for improved immunomodulators which exploit the unique features of DC targeting and activation of SAgs to deliver and enhance the T cell recognition of antigens such as peptides that are normally non-immunogenic or have low immunogenicity, yet are efficacious and have low toxicity.
It is an object of the present invention to overcome or ameliorate at least some of the disadvantages of the prior art, or to provide a useful alternative.